The MUC2 Mucus Gel as an Innate Immune Mechanisms that Inhibits Colitis

描述（由申请人提供）：覆盖我们粘膜表面的粘液是先天免疫系统的重要组成部分，也是抵御微生物挑战的第一道防线。这在肠道的下部尤其突出，在那里我们必须保护自己，同时我们生活在共生关系中，而不会引发明显的免疫反应。在一份趋势性出版物（PNAS，2008）中，我们可以表明结肠具有围绕MUC 2粘蛋白构建的双层粘液层。这些内部充当屏障，不允许细菌渗透。在粘液中缺乏MUC 2或缺陷的情况下，细菌到达上皮细胞，渗透到隐窝中，并进入上皮细胞。在实验性结肠炎中，细菌可以穿透内部致密的粘液层，进一步证明这是理解肠道炎症和溃疡性结肠炎的关键。我们现在将研究粘液层是如何形成的，并通过使用生物化学方法，特别是质谱法，以及使用各种类型的基因敲除动物，这些动物被细菌或无菌定植。通过对活检粘液层生长的研究，我们将描述引起溃疡性结肠炎的改变。粘液性质将通过重组粘液蛋白和药理学试剂来操纵。预期结果是改善结肠保护的新方法，并通过这种新原理治疗溃疡性结肠炎。目标1。了解粘液及其主要成分MUC 2粘蛋白如何保护结肠和小肠的粘膜表面。大肠中松散和坚固的结肠粘液的分泌，形成和组分及其过渡这包括对生物合成，0-糖基化，解包/分泌，体积膨胀，附着于上皮细胞和免疫系统调节的理解。目标2.阐明MUC 2粘蛋白及其聚糖在结肠黏膜细菌植物群选择中的作用以及细菌对内粘液层的影响。目标3。为了阐明结肠内粘液层在溃疡性结肠炎（UC）疾病中的作用。

DESCRIPTION (provided by applicant): The mucus covering our mucosal surfaces is an intimate part of the innate immune system and the first line of defense against microbial challenges. This is especially prominent in the lower parts of the intestine where we have to protect ourselves at the same time as we live in a symbiotic relation without trigger an overt immune response. In a trend-setting publication (PNAS, 2008) we could shown that colon has a double- layered mucus layer built around the MUC2 mucin. The inner of these act as a barrier and does not allow bacteria to penetrate. With an absence of MUC2 or defects in the mucus, bacteria reach the epithelial cells, penetrate into the crypts, and into the epithelial cells. In experimental colitis the bacteria can penetrate this inner dense mucus layer further proving that this is the key to an understanding of intestinal inflammation and ulcerative colitis. We will now study how the mucus layers are formed and built by the use of biochemical methods, especially mass spectrometry, and the use of various types of gene knock-out animals that are colonized with bacteria or germ-free. By studies on the growth of the mucus layers from biopsies we will characterize the alterations causing ulcerative colitis. The mucus properties will be manipulated by recombinant mucus proteins and pharmacological agents. Expected results are novel ways to improve the protection of colon and by this novel principle for treatment of the disease ulcerative colitis. Aim 1. To obtain a functional understanding of how the mucus and its main component, the MUC2 mucin, protect the mucosal surfaces of the colon and small intestine. Secretion, formation and components of the loose and firm colonic mucus in the large intestine and its transition This includes an understanding of biosynthesis, 0-glycosylation, unpacking/secretion, volume expansion, attachment to epithelia, and regulation by immune system. Aim 2. To unravel the role of the MUC2 mucin and its glycans in the selection of our colonic commensal bacterial flora and effects of bacteria on the inner mucus layer. Aim 3. To unravel the role of the inner colonic mucus layer in the disease Ulcerative Colitis (UC).